Innate lymphoid cells (ILCs) are developmentally related cells that play an important role in innate defenses and tissue remodeling. So far, only natural killer (NK) cells have been identified and ...functionally characterized in human decidua where they contribute to induction of immune suppression, neo-angiogenesis, and tissue building/remodeling. The presence of other ILC subsets in human decidua has not been yet characterized. Here we identify in human decidua, during early pregnancy, two subsets of decidual group 3 ILC (ILC3), including lymphoid tissue inducer (LTi)-like cells and natural cytotoxicity receptors (NCRs)(+)ILC3 and interferon-(IFN)γ-producing ILC1, different from NK cells. Decidual LTi-like cells produced interleukin -17 (IL-17) and tumor necrosis factor (TNF), while NCR(+)ILC3 released IL-22 and IL-8. Importantly, NCR(+)ILC3 and LTi-like cells established functional interactions with stromal cells. Decidual LTi-like cells differentiated into NCR(+)ILC3, whereas they marginally contributed to NK cell generation. Our data suggest that decidual ILC3 may play a role in innate defenses and in vessel and tissue building, thus contributing to maintenance of pregnancy.
Innate lymphoid cells (ILCs) have a central role in innate defenses against pathogens, lymphoid organogenesis, and tissue remodeling. They have been detected in human decidua, however, their role in ...this tissue remains unclear. Successful pregnancy requires an early inflammatory phase favoring implantation and tissue remodeling as well as a subsequent regulatory phase to prevent fetal rejection and supporting neoangiogenesis. Here, we show that, during the first trimester of pregnancy, neutrophils infiltrate decidua basalis and are more abundant in normal pregnancy than in spontaneous miscarriages. Decidual neutrophils localize in proximity of NCR
ILC3, which may influence neutrophil migration and survival given their production of CXCL8 and granulocyte macrophage colony-stimulating factor (GM-CSF). Moreover, NCR
ILC3-derived GM-CSF was found to induce the expression of heparin-binding EGF-like growth factor and IL1ra in neutrophils, two proteins/cytokines involved in tissue remodeling and maintenance of pregnancy. Our data suggest that the simultaneous presence of NCR
ILC3 and neutrophils in decidual tissues and their possible cross talk, may have a role in the early phases of pregnancy.
Natural killer cells can discriminate between normal cells and cells that do
not express adequate amounts of major histocompatibility complex (MHC) class I
molecules. The discovery, both in mouse and ...in human, of MHC-specific
inhibitory receptors clarified the molecular basis of this important NK cell
function. However, the triggering receptors responsible for positive NK cell
stimulation remained elusive until recently. Some of these receptors have now
been identified in humans, thus shedding some light on the molecular mechanisms
involved in NK cell activation during the process of natural cytotoxicity.
Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and
NKp44) have been identified. They represent the first members of a novel
emerging group of receptors collectively termed natural cytotoxicity receptors
(NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the
NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be
virtually abrogated by the simultaneous masking of the three NCRs. There is a
coordinated surface expression of the three NCRs, their surface density varying
in different individuals and also in the NK cells isolated from a given
individual. A direct correlation exists between the surface density of NCR and
the ability of NK cells to kill various tumors. NKp46 is the only NCR involved
in human NK-mediated killing of murine target cells. Accordingly, a homologue
of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel
members of the Ig superfamily displaying a low degree of similarity to each
other and to known human molecules. NCRs are coupled to different signal
transducing adaptor proteins, including CD3ζ, Fc∍RIγ, and
KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either
a complementary or a synergistic role with NCRs. Thus, the triggering of NK
cells in the process of tumor cell lysis may often depend on the concerted
action of NCR and NKG2D. In some instances, however, it may uniquely depend
upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be
appreciated using clones that, in spite of their NCR
dull
phenotype,
efficiently lyse certain epithelial tumors or leukemic cell lines. Other
triggering surface molecules including 2B4 and the novel NKp80 appear to
function as coreceptors rather than as true receptors. Indeed, they can induce
natural cytotoxicity only when co-engaged with a triggering receptor. While an
altered expression or function of NCR or NKG2D is being explored as a possible
cause of immunological disorders, 2B4 dysfunction has already been associated
with a severe form of immunodeficiency. Indeed, in patients with the X-linked
lymphoproliferative disease, the inability to control Epstein-Barr virus
infections may be consequent to a major dysfunction of 2B4 that exerts
inhibitory instead of activating functions.
Immune checkpoint inhibitors have revolutionized cancer therapy leading to exceptional success. However, there is still the need to improve their efficacy in non‐responder patients. Natural killer ...(NK) cells represent the first line of defence against tumours, due to their ability to release immunomodulatory cytokines and kill target cells that have undergone malignant transformation. Harnessing NK cell response will open new possibilities to improve control of tumour growth. In this respect inhibitory checkpoints expressed on these innate lymphocytes represents a promising target for next‐generation immunotherapy. In this review, we will summarize recent evidences on the expression of NK cells receptors in cancer, with a focus on the inhibitory checkpoint programmed cell death protein 1 (PD‐1). We will also highlight the strength and limitations of the blockade of PD‐1 inhibitory pathway and suggest new combination strategies that may help to unleash more efficiently NK cell anti‐tumour response.
After the discovery, in humans and mice, of inhibitory natural killer (NK) receptors specific for MHC class I molecules, the mechanism by which NK cells kill tumor or virus-infected cells was thought ...to be clarified: NK cells would kill those target cells that have lost, or underexpress, MHC class I molecules. However, a more complex scenario has recently emerged. For example, certain NK cells express insufficient amounts of triggering receptors, and target cells can lack ligands for such receptors. Thus, it appears that the activation of NK cells and their potentially harmful effector functions are under the control of different checkpoints.
In recent years, mesenchymal stem cells (MSCs) have been shown to inhibit T-lymphocyte proliferation induced by alloantigens or mitogens. However, no substantial information is available regarding ...their effect on natural killer (NK) cells. Here we show that MSCs sharply inhibit IL-2-induced proliferation of resting NK cells, whereas they only partially affect the proliferation of activated NK cells. In addition, we show that IL-2-activated NK cells (but not freshly isolated NK cells) efficiently lyse autologous and allogeneic MSCs. The activating NK receptors NKp30, NKG2D, and DNAM-1 represented the major receptors responsible for the induction of NK-mediated cytotoxicity against MSCs. Accordingly, MSCs expressed the known ligands for these activating NK receptors—ULBPs, PVR, and Nectin-2. Moreover, NK-mediated lysis was inhibited when IFN-γ-exposed MSCs were used as target cells as a consequence of the up-regulation of HLA class I molecules at the MSC surface. The interaction between NK cells and MSCs resulted not only in the lysis of MSCs but also in cytokine production by NK cells. These results should be taken into account when evaluating the possible use of MSCs in novel therapeutic strategies designed to improve engraftment or to suppress graft-versus-host disease (GVHD) in bone marrow transplantation.
The term of "natural killer" (NK) cells was originally assigned on a merely functional basis to lymphoid cells capable of lysing certain tumors in the absence of prior stimulation. However, both ...their origin and the molecular mechanism(s) involved in their function remained a mystery for many years 1. Regarding their origin, clear evidence has now been provided both inmouse and in man that NK and T cells may derive from a common precursor 2–5. Thus, mature NK cells can be obtained in vitro from CD34+ cells isolated from umbilical cord blood, bone marrow (BM) and even human thymus 6 when cultured in the presence of appropriate feeder cells or IL‐15. The molecular mechanism allowing NK cells to discriminate between normal and tumor cells, predicted by the "missing self hypothesis" 7, has been clarified only in recent years. Thus, NK cells recognize MHC class I molecules through surface receptors delivering signals that inhibit, rather than activate, NK cells. As a consequence, NK cells lyse target cells that have lost (or express insufficient amounts of) MHC class I molecules, as frequently occurs in tumors and in cells infected by certain viruses.
Experimental and clinical data suggest that tumours harbour a cell population retaining stem cell characteristics that can drive tumorigenesis. CD133 is considered an important cancer stem cells ...(CSC)-associated marker. In a large variety of human malignancies, including melanoma, CD133+ cells have been reported to comprise CSC. In this study, we show that melanoma cell lines are highly heterogeneous for the expression of several stem cell-associated markers including CD133, c-kit/CD117 and p75 neurotrophin receptor/CD271. Since no information is available on the ability of NK cells to recognize and lyse melanoma stem cells, we assessed whether melanoma cell lines, characterized by stem cell-like features, were susceptible to lysis by IL-2-activated NK cells. We show that activated NK cells efficiently kill malignant melanoma cell lines that were enriched in putative CSC by the use of different selection methods (i.e. CD133 expression, radioresistance or the ability to form melanospheres in stem cell-supportive medium). NK cell-mediated recognition and lysis of melanoma cells involved different combinations of activating NK receptors. Since CSC have been reported to be both drug resistant and radioresistant, our present data suggest that NK-based adoptive immunotherapy could represent a novel therapeutic approach to possibly eradicate metastatic melanoma.
Natural Killer (NK) cells are capable of recognizing and killing cancer cells and play an important role in tumor immunosurveillance. However, tumor-infiltrating NK cells are frequently impaired in ...their functional capability. A remarkable exception is represented by NK cells isolated from malignant pleural effusions (PE) that are not anergic and, upon IL2-induced activation, efficiently kill tumor cells. Although IL2 is used in various clinical trials, severe side effects may occur in treated patients. In this study, we investigated whether also other clinical-grade cytokines could induce strong cytotoxicity in NK cells isolated from pleural fluid of patients with primary or metastatic tumors of different origins. We show that PE-NK cells, cultured for short-time intervals with IL15, maintain the CD56
bright
phenotype, a high expression of the main activating receptors, produce cytokines and kill tumor cells in vitro similarly to those treated with IL2. Moreover, IL15-activated PE-NK cells could greatly reduce the growth of established tumors in mice. This in vivo antitumor effect correlated with the ability of IL15-activated PE-NK cells to traffic from periphery to the tumor site. Finally, we show that IL15 can counteract the inhibitory effect of the tumor pleural microenvironment. Our study suggests that IL15-activated NK cells isolated from pleural fluid (otherwise discarded after thoracentesis) may represent a suitable source of effector cells to be used in adoptive immunotherapy of cancer.
Trophoblastic cells lack classical HLA class I and class II molecules but express HLA-G1. Although this may prevent allorecognition by maternal T cells, it renders trophoblastic cells potentially ...susceptible to lysis by natural killer (NK) cells. As shown here, only a fraction of peripheral-blood NK cells in pregnant women express the HLA-G1-specific CD94/NKG2A and/or LIR-1 receptors. However, all NK cells isolated from maternal decidua during the first trimester expressed either one or both of these receptors. Perhaps more importantly, a fraction of cells expressed p49, an HLA-G1-specific inhibitory receptor, undetectable in peripheral-blood NK cells. p49 was expressed on virtually all NK cells isolated from placenta at term. Functional analyses revealed that the HLA class I-negative 221 lymphoblastoid cell line transfected with HLA-G1 was only partially protected from lysis by peripheral-blood NK cells isolated from pregnant women, whereas it was fully protected from decidual NK cells. As indicated by the addition of specific antibodies to cytolytic tests, all the above receptors contributed to HLA-G1 recognition by decidual NK cells, although p49 would appear to play a predominant role.
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